By Naim Alkhouri, MD, FAASLD, DABOM.
Known as a “silent disease”, metabolic dysfunction-associated steatohepatitis (MASH) is affecting a growing number of people, with an expected 27 million cases in the United States by 2030.1 That’s an alarming increase of 63 percent since 2015, and yet the numbers do not begin to tell the full story of the burden of this disease.2
MASH, formerly known as nonalcoholic steatohepatitis (NASH), is a chronic and progressive disease in which fat accumulates in the liver. This causes inflammation and ultimately leads to fibrosis – scarring that occurs when the liver attempts to repair and replace damaged cells. This liver damage can result in severe complications, including cirrhosis, liver failure or liver cancer.3 Around 20% of patients with MASH progress to cirrhosis.4 This progression is particularly concerning due to the significantly greater level of care required which compounds the burden on both the patient and the healthcare system.5 Recently, a study that used decision analytical modeling to stimulate the MASH natural history predicted significant increases by 2050 in the number of cases of MASH leading to liver cancer (increase from 11,483 cases in 2020 to 22,440 by 2050) and liver transplantation (increase from 1,717 case in 2020 to 6,720 by 2050).6
Despite the growing number of people with MASH, there is currently only one FDA-approved treatment for the disease. Treatment of this patient population is further complicated because many people with MASH have other cardiometabolic comorbidities.1 The primary treatment goal for patients with MASH at all stages is reversal of liver fibrosis to prevent progression to cirrhosis, decompensation or liver cancer.3 And there are currently no approved treatment options for cirrhosis. Therefore, there is an urgent need for treatments that reduce fibrosis in the liver, are effective for cirrhotic MASH, and successfully target other metabolic disturbances.
A novel approach in FGF21s
There are currently multiple treatment modalities being investigated in clinical trials for MASH, with one method targeting the fibroblast growth factor 21 (FGF21) signaling pathway. FGF21 is an endogenous hormone produced by the liver with far reaching effects on energy expenditure and glucose and lipid metabolism. Importantly, FGF21 possesses anti-fibrotic effects making it an ideal target for MASH treatments. However, native FGF21’s short half-life makes it unfit for therapeutic uses.
One company focusing on FGF21 is 89bio whose long-acting FGF21 analog, pegozafermin, is currently in late-stage clinical trials. Pegozafermin addresses the short half-life of native FGF21 through novel glycoPEGylation technology that successfully prolongs activity and site-specific mutations that prevent breakdown. Importantly, as an FGF21 analog, pegozafermin targets the underlying causes of MASH both within the liver and throughout the body. Pegozafermin utilizes two metabolic pathways in the body. One pathway aids in reducing fat accumulation and inflammation, the drivers of fibrosis, and the other pathway supports anti-inflammatory and anti-fibrotic effects.
Pegozafermin is being investigated for MASH in two ongoing Phase 3 trials. The first, ENLIGHTEN-Fibrosis, includes MASH patients with moderate to advanced fibrosis (stages F2-F3) and the second, ENLIGHTEN-Cirrhosis, includes MASH patients with compensated cirrhosis (stage F4). In clinical trials thus far, pegozafermin has demonstrated reversal of fibrosis, MASH resolution, reduction of liver fat and improved insulin resistance. In MASH patients with compensated cirrhosis, achieving fibrosis regression is a challenging yet crucial goal. Pegozafermin has great potential for this patient population through its potent anti-fibrotic effects.
Given the disease’s progressive, chronic nature and asymptomatic quality in early stages, treatment options that support patient compliance and persistency are particularly important. Pegozafermin demonstrated a favorable tolerability and safety profile, with mild gastrointestinal side effects and no clinically significant changes in vitals or bone biomarkers. Additionally, pegozafermin can be self-administered as a single subcutaneous injection weekly or once every other week, suggesting it could offer a convenient and preferred option for people who may already be on multiple medicines due to comorbidities.
The urgency of delivering safe and effective treatments for patients with advanced stages of MASH contributes to an environment of pushing boundaries while following the science. In the last two years we have witnessed great momentum. From the significant progress of companies such as 89bio, investigating innovative approaches, to the first ever MASH-approved therapy, the future holds promise for more life-changing targeted and potent therapies to come.
References:
- Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J, Vos MB. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology. 2019 Jun;69(6):2672-2682. doi: 10.1002/hep.30251. PMID: 30179269.
- Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1. PMID: 28802062; PMCID: PMC5767767.
- Alkhouri N, Noureddin M. Management strategies for metabolic dysfunction-associated steatotic liver disease (MASLD). Am J Manag Care. 2024 Nov;30(9 Suppl):S159-S174. doi: 10.37765/ajmc.2024.89635. PMID: 39513734
- Luthra R, Sheth A. Understanding MASH: An Examination of Progression and Clinical Outcomes by Disease Severity in the TARGET-NASH Database. Adv Ther. 2025 Feb;42(2):1165-1195. doi: 10.1007/s12325-024-03085-4. Epub 2024 Dec 30. PMID: 39739194; PMCID: PMC11787050.
- Fishman JC, Qian C, Kim Y, Rochon H, Szabo SM, Sun R, Charlton M. Cost burden of cirrhosis and liver disease progression in metabolic dysfunction-associated steatohepatitis: A US cohort study. J Manag Care Spec Pharm. 2024 Sep;30(9):929-941. doi: 10.18553/jmcp.2024.24069. Epub 2024 Jun 7. PMID: 38845444; PMCID: PMC11365567.
- Le P, Tatar M, Dasarathy S, Alkhouri N, Herman WH, Taksler GB, Deshpande A, Ye W, Adekunle OA, McCullough A, Rothberg MB. Estimated Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease in US Adults, 2020 to 2050.JAMA Netw Open. 2025 Jan 2;8(1):e2454707. doi: 10.1001/jamanetworkopen.2024.54707. PMID: 39821400